1. Field of the Invention
The present invention relates to novel substituted imidazoles, to the use of these compounds as medicaments, to pharmaceutical compositions comprising the compounds, and to a method of treatment employing these compounds and compositions. The present compounds show a high and selective binding affinity to the histamine H3 receptor indicating histamine H3 receptor antagonistic or agonistic activity. As a result, the compounds are useful for the treatment and/or prevention of diseases and disorders related to the histamine H3 receptor.
2. Description of the Related Art
The existence of the histamine H3 receptor has been known for several years and of current interest for the development of new medicaments (see e.g. Stark, H.; Schlicker, E.; Schunack, W., Drugs Fut. 1996, 21, 507-520; Leurs, R.; Timmerman, H.; Vollinga, R. C., Progress in Drug Research 1995, 45, 107-165). Recently, the histamine H3 receptor has been cloned, cf. Lovenberg, T. W. et al, Molecular Pharmacology, June 1999, 55, 1101-1107. The histamine H3 receptor is a presynaptic autoreceptor located in both the central and the peripheral nervous systems, the skin, and in organs such as the lung, the intestine, probably the spleen and the gastrointestinal tract. The histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. A histamine H3 receptor antagonist would therefore be expected to increase the release of these neurotransmitters in the brain. A histamine H3 receptor agonist, on the contrary, leads to an inhibition of the biosynthesis of histamine and an inhibition of the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists and antagonists could be important mediators of neuronal activity. Accordingly, the histamine H3 receptor is an important target for new therapeutics.
Imidazoles similar to the compounds of the present invention have previously been prepared, and their biological properties have been investigated. Thus, WO 98/29119 relates to tetrahydroimidazopyridine farnesyl-protein inhibitors. JP 06312927 discloses tetrahydroimidazopyridine intermediates for preparing angiosin II inhibitors. WO 93/17701 discloses tetrahydroimidazopyridine intermediates for preparing endothelin receptor-binding peptides. Klutchko, S., et al., J. Heterocycl. Chem., 28(1), 1991, 97-108 relates to synthesis methods for the preparation of imidazole derivatives. GB 2158440 relates to antiviral compounds. Arcari, G.; Bernardi, L.; Cimaschi, R.; Falconi, G.; Luini, F.; Scarponi, U., Arzneim. Forsch., 34, 11, 1984, 1467-1471, relates to tetrahydroimidazopyridine intermediates for the preparation of imidazopiperidines with anti-ulcer and antisecretory activity, and GB 2028798 relates to tetrahydroimidazopyridine intermediates for the preparation of antiulcer and anticholinergic compounds. However, these references neither disclose nor suggest that the imidazoles may have a histamine H3 receptor antagonistic or agonistic activity.
Furthermore, Chem. Abstr., 87, 201535; Hepp, M.; Schunack, W., Arch. Pharm. (Weinheim Ger.), 313, 9, 1980, 756-762; Vitali et al., Farmaco Ed. Sci., 22, 1967, 821; Habermehl; Ecsy, Heterocycles, 5, 1976, 127; Vitali; Bertaccini, Gazz. Chim. Ital., 94, 1964, 296; Emmett, J. C.; Durant, G. J.; Ganellin, C. R.; Roe, A. M.; Turner, J. L., J. Med. Chem., 25, 10, 1982, 1168-1174; Nagarajan, K. et al., Indian J. Chem. Sect. B, 15, 1977, 629-634; Casella, L.; Gullotti, M., J. Am. Chem. Soc., 103, 21, 1981, 6338-6347; Piper, I. M.; MacLean, D. B.; Kvarnstroem, I.; Szarek, W. A., Can. J. Chem., 61, 1983, 2721-2728; Williams, R. L.; Neergaard, S., J. Pharm. Sci., 71, 1, 1982, 119-120), DE 2700012, EP 589 665, EP 531 874, WO 92/18115, EP 449 521, U.S. Pat. No. 5,091,390, DE 33 02 125 and DE 33 02 126 disclose imidazopyridine derivatives which are stated to be useful either as intermediates or as therapeutically active substances such as angiotensin II antagonists effective to treat hypertension, peripheral kappa opioid receptor activating substances effective to treat inflammatory pain and N-myristoyl transferase inhibitors effective as anti-cancer agents. However, these references neither disclose nor suggest that the imidazoles may have a histamine H3 receptor antagonistic or agonistic activity.
Several publications disclose the preparation and use of histamine H3 agonists and antagonists. Thus, U.S. Pat. No. 4,767,778 (corresponding to EP 214 058), EP 338 939, WO 93/14070, EP 531 219, EP 458 661, EP 197 840, EP 494 010, WO 91/17146, WO 93/12108, WO 93/12107, WO 93/12093, U.S. Pat. No. 5,578,616 (corresponding to WO 95/14007), WO 96/38142, WO 96/38141, WO 95/11894, WO 93/20061, WO 96/40126, WO 95/06037, WO 92/15567 and WO 94/17058 disclose imidazole derivatives having histamine H3 receptor agonistic or antagonistic activity. However, the structures of these imidazole derivatives are quite different from that of the present compounds. Thus, none of the imidazole derivatives disclosed in these publications have a ring structure fused to the imidazole group such as is the case in the present compounds.
In view of the art's interest in histamine H3 receptor agonists and antagonists, novel compounds which interact with the histamine H3 receptor would be a highly desirable contribution to the art. The present invention provides such a contribution to the art being based on the finding that a specific class of substituted imidazole compounds has a high and specific affinity to the histamine H3 receptor. Some of these substituted imidazole derivatives are novel per se, thereby constituting a further aspect of the invention.
Due to their interaction with the histamine H3 receptor, the present compounds are useful in the treatment and/or prevention of a wide range of conditions and disorders in which an interaction with the histamine H3 receptor is beneficial. Thus, the compounds may find use, e.g., in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinologic system.
Definitions
In the structural formulas given herein and throughout the present specification, the following terms have the indicated meaning:
The term “C1-6-alkyl” as used herein represents a branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Typical C1-6-alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
The term “C2-8-alkenyl” as used herein represents a branched or straight hydrocarbon group having from 2 to 8 carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, allyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-heptenyl, 1-octenyl, 2-octenyl, and the like. In a similar way the term “C2-6-alkenyl” represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond.
The term “C2-8-alkynyl” as used herein represents a branched or straight hydrocarbon group having from 2 to 8 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 1-heptynyl, 2-heptynyl, 1-octynyl, 2-octynyl, and the like. In a similar way the term “C2-6-alkynyl” represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond.
The term “C1-6-alkoxy” as used herein, alone or in combination, refers to the radical —O—C1-6-alkyl where C1-6-alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, and the like.
The term “C1-6-alkylthio” as used herein, alone or in combination, refers to the radical —S—C1-6-alkyl where C1-6-alkyl is as defined above. Representative examples are methylthio, ethylthio, isopropylthio, propylthio, butylthio, pentylthio, and the like.
The term “C3-15-cycloalkyl” as used herein represents a carbocyclic group having from 3 to 15 carbon atoms such as from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecy, and the like. In the same way the term “C3-8-cycloalkyl” represents a carbocyclic group having from 3 to 8 carbon atoms.
The term “C3-15-cycloalkenyl” as used herein represents a carbocyclic group having from 3 to 15 carbon atoms, such as from 3 to 8 carbon atoms, and at least one double bond. Representative examples are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohepentyl, cyclooctenyl, cyclononenyl, cyclodecenyl, and the like.
The term “C3-15-cycloalkynyl” as used herein represents a carbocyclic group having from 3 to 15 carbon atoms, such as from 3 to 8 carbon atoms, and at least one triple bond. Representative examples are cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl, cycloheptynyl, cyclooctynyl, cyclononynyl, cyclodecynyl, and the like.
The term “aryl” as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, naphthyl(1-naphthyl or 2-naphthyl), anthracenyl(1-anthracenyl, 2-anthracenyl, 3-anthracenyl), phenanthrenyl, fluorenyl, indenyl, and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1-(1,2,3,4-tetrahydronaphthyl) and 2-(1,2,3,4-tetrahydronaphthyl).
The term “aroyl” as used herein refers to the radical —CO-aryl where aryl is as defined above. Non-limiting examples are benzoyl, naphthoyl, anthracenoyl, phenanthrenoyl, fluorenoyl, indenoyl, and the like.
The term “aryloxy” as used herein refers to the radical —O-aryl where aryl is as defined above. Non-limiting examples are phenoxy, naphthoxy, anthracenyloxy, phenantrenyloxy, fluorenyloxy, indenyloxy, and the like.
The term “arylthio” as used herein refers to the radical —S-aryl where aryl is as defined above. Non-limiting examples are phenylthio, naphthylthio, phenanthrenylthio, fluorenylthio, indenylthio, and the like.
The term “arylamino” as used herein refers to the radical —NH-aryl where aryl is as defined above. Non-limiting examples are phenylamino, naphthylamino, phenanthrenylamino, fluorenylamino, indenylamino, and the like.
The term “arylsulfonyl” as used herein refers to the radical —S(═O)2-aryl where aryl is as defined above. Non-limiting examples are phenylsulfonyl, naphthylsulfonyl, phenanthrenylsulfonyl, fluorenylsulfonyl, indenylsulfonyl, and the like.
The term “heteroaryl” as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzothiophenyl(thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, and the like. Heteroaryl is also intended to include the partially or fully hydrogenated derivatives of the heterocyclic systems enumerated above. Non-limiting examples of such partially or fully hydrogenated derivatives are pyrrolinyl, pyrazolinyl, indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, oxazolinyl, oxazepinyl, aziridinyl and tetrahydofuranyl.
The term “heteroaroyl” as used herein refers to the radical —CO-heteroaryl where heteroaryl is as defined above. Non-limiting examples are furoyl, thienylcarbonyl, pyridoyl, oxazolylcarbonyl, benzofurylcarbonyl, benzimidazolylcarbonyl, pyrrolinylcarbonyl, azepinylcarbonyl, and the like.
The term “heteroaryloxy” as used herein refers to the radical —O-heteroaryl where heteroaryl is as defined above. Non-limiting examples are furyloxy, thienyloxy, pyridyloxy, oxazolyloxy, benzofuryloxy, benzimidazolyloxy, pyrrolinyloxy, azepinyloxy, and the like.
The term “heteroarylamino” as used herein refers to the radical —NH-heteroaryl where heteroaryl is as defined above. Non-limiting examples are furylamino, thienylamino, pyridylamino, oxazolylamino, benzofurylamino, benzimidazolylamino, pyrrolinylamino, azepinylamino, and the like.
The term “heteroarylthio” as used herein refers to the radical —S-heteroaryl where heteroaryl is as defined above. Non-limiting examples are furylthio, thienylthio, pyridylthio, oxazolylthio, benzofurylthio, benzimidazolylthio, pyrrolinylthio, azepinylthio, and the like.
The term “heteroarylsulfonyl” as used herein refers to the radical —S(═O)2-heteroaryl where heteroaryl is as defined above. Non-limiting examples are furylsulfonyl, thienylsulfonyl, pyridylsulfonyl, oxazolylsulfonyl, benzofurylsulfonyl, benzimidazolylsulfonyl, pyrrolinylsulfonyl, azepinylsulfony, and the like.
The term “acylamino” as used herein represents a radical of the form —N(L)—C(═O)—G where G and L independently represent hydrogen, C1-6-alkyl, aryl or heteroaryl as defined above. Non-limiting examples are acetylamino, propanoylamino, butyrylamino, pentanoylamino, benzoylamino, furoylamino, pyridoylamino, and the like.
The term “sulfonylamino” as used herein represents a radical of the form —N(L)—S(═O)2—G where G and L independently represent hydrogen, C1-6-alkyl, aryl or heteroaryl as defined above. Non-limiting examples are methanesulfonylamino, propanesulfonylamino, benzenesulfonylamino, N-methyl-N-(benzenesulfonyl)amino, 4-methylbenzenesulfonylamino N-butyl-N-(4-methylbenzenesulfonyl)amino, 2-thienylsulfonylamino, and the like.
The term “halogen” means fluorine, chlorine, bromine or iodine.
As used herein, the phrase “3 to 8-membered, saturated or unsaturated, carbocyclic or heterocyclic ring” is intended to include carbocyclic rings which are saturated or contain one or more double bonds as well as heterocyclic rings containing one or more heteroatoms selected from nitrogen, oxygen or sulfur which are saturated or contain one or more double bonds.
Certain of the above defined terms may occur more than once in the structural formulas, and upon such occurrence each term shall be defined independently of the other.
The term “optionally substituted” as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.
As used herein, the phrase “a functional group which can be converted to hydrogen in vivo” is intended to include any group which upon administering the present compounds to the subjects in need thereof can be converted to hydrogen, e.g., enzymatically or by the acidic environment in the stomach. Non-limiting examples of such groups are acyl, carbamoyl, monoalkylated carbamoyl, dialkylated carbamoyl, alkoxycarbonyl, alkoxyalkyl groups, and the like, such as C1-6-alkanoyl, aroyl, C1-6-alkylcarbamoyl, di-C1-6-alkylcarbamoyl, C1-6-alkoxycarbonyl and C1-6-alkoxy-C1-6-alkyl.
As used herein, the phrase “diseases and disorders related to the histamine H3 receptor” is intended to include any disease or disorder in which an effect, either antagonistic or agonistic, on the histamine H3 receptor is beneficial.